Interleukin-10 inhibits interferon-gamma-induced intercellular adhesion molecule-1 gene transcription in human monocytes
Interleukin-10 inhibits interferon-gamma-induced intercellular adhesion molecule-1 gene transcription in human monocytes
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DOI：
10.1182/blood.v89.12.4461
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发表时间：
1997-06-15
期刊：
影响因子：
20.3
通讯作者：
Finnegan, A
中科院分区：
文献类型：
--
作者：
Song, S;LingHu, H;Finnegan, A
白细胞介素-10（IL-10）是一种有效的单核细胞调节因子，可抑制促炎介质的基因表达。本研究探讨了IL-10下调干扰素-γ（IFN-γ）激活的正常人单核细胞表面细胞间粘附分子-1（ICAM-1）表达的机制。IL-10对IFN-γ诱导的ICAM-1表达的抑制早在3小时就明显，并且被抗IL-10抗体阻断，但不被同种型匹配的对照抗体阻断。北方印迹分析显示IL-10减少IFN-γ刺激的单核细胞中ICAM-1 mRNA的积累，在3小时检测到IL-10对ICAM-1稳态mRNA的抑制，并保持在24小时。核连续转录分析显示IL-10抑制IFN-γ诱导的ICAM-1基因转录的速率，mRNA稳定性研究显示IL-10不改变IFN-γ诱导的ICAM-1信息的半衰期。因此，IL-10主要在基因转录水平抑制IFN-γ诱导的单核细胞中ICAM-1表达。IFN-γ应答基因的激活需要转录因子STAT-1 α（信号转导和转录激活因子-1 α）的酪氨酸磷酸化。然而，IL-10不影响IFN-γ诱导的STAT-1 α酪氨酸磷酸化或改变STAT-1 α与ICAM-1启动子中IFN-γ应答元件（IRE）的结合。相反，IL-10阻止了IFN-γ诱导的ICAM-1启动子中肿瘤坏死因子α（TNF-α）应答性NF-κ B/C-EBP复合元件的NF-κ B位点的结合活性。这些数据表明IL-10通过可能涉及NF-κ B的调节机制抑制IFN-γ诱导的ICAM-1基因转录。(C)1997年，美国血液学会。
Interleukin-10 (IL-10) is a potent monocyte regulatory cytokine that inhibits gene expression of proinflammatory mediators, In this study, we investigated the mechanism by which IL-10 downregulates expression of intercellular adhesion molecule-1 (ICAM-1) on the cell surface of normal human monocytes activated with interferon-gamma (IFN-gamma). IL-10 inhibition of IFN-gamma-induced ICAM-1 expression was apparent as early as 3 hours and was blocked by an anti-IL-10 antibody but not by an isotype-matched control antibody. Northern blot analysis showed that IL-10 reduced the accumulation of ICAM-1 mRNA in IFN-gamma-stimulated monocytes, IL-10 inhibition of ICAM-1 steady-state mRNA was detected at 3 hours and remained at 24 hours, Nuclear run-on transcription assays showed that IL-10 inhibited the rate of IFN-gamma-induced transcription of the ICAM-1 gene, and mRNA stability studies showed that IL-10 did not alter the half-life of IFN-gamma-induced ICAM-1 message. Thus, IL-10 inhibits IFN-gamma-induced ICAM-1 expression in monocytes primarily at the level of gene transcription. Activation of IFN-gamma-responsive genes requires tyrosine phosphorylation of the transcriptional factor STAT-1 alpha (signal transducer and activator of transcription-1 alpha). However, IL-10 did not affect IFN-gamma-induced tyrosine phosphorylation of STAT-1 alpha or alter STAT-1 alpha binding to the IFN-gamma response element (IRE) in the ICAM-1 promoter. Instead, IL-10 prevented IFN-gamma-induced binding activity at the NF-kappa B site of the tumor necrosis factor alpha (TNF-alpha)-responsive NF-kappa B/C-EBP composite element in the ICAM-1 promoter. These data indicate that IL-10 inhibits IFN-gamma-induced transcription of the ICAM-1 gene by a regulatory mechanism that may involve NF-kappa B. (C) 1997 by The American Society of Hematology.